Adicet Bio Inc Aktie

Hello, everyone, and welcome to the Adicet webcast. [Operator Instructions] This call is being recorded, and the slides are available on the Investors section of the company's corporate website. I'll now turn the call over to Chen Schor, CEO of Adicet Bio. Go ahead.

Good morning, everyone, and thank you for joining us today. This morning, we announced positive data for prula-cel, and we now look forward to discussing the results.

Joining me today is Dr. Lloyd Klickstein, our Interim Chief Medical Officer and a member of our Board of Directors, who will summarize the clinical data to date supporting our decision to advance prula-cel into a pivotal study.

After that, we'll be joined by Dr. Blake Aftab, our Chief Scientific Officer, to discuss the supporting evidence of immune reset observed in our clinical study.

And then we'll open it up for Q&A, where we will be joined by Nick Harvey, our Chief Financial Officer. Please note that today's call may include forward-looking statements based on our current expectations. These statements represent our judgment as of today and inherently involve risks and uncertainties that may cause actual results to differ materially from results discussed.

Please refer to our filings with the Securities and Exchange Commission for more information. Today is a very exciting day for Adicet and more importantly, for patients as we share promising data that demonstrated compelling safety and efficacy results for prula-cel in patients with systemic lupus erythematosus or SLE with or without lupus nephritis.

In heavily pretreated patient population at the 12-month mark, 50% of evaluable lupus nephritis patients achieved complete renal response and 54% of the overall lupus population achieved DORIS remission.

Importantly, these remissions were achieved with a generally highly favorable safety profile with no IEC-HS, no ICANS and no CRS above Grade 2. We understand the biology underlying prula-cel's favorable safety profile and its differentiation from the safety profile of alpha-beta CAR-T therapies, as you will see in the slides ahead.

All patients discontinued immunosuppressants and all but one patient tapered back on steroids to 5 milligram or less of prednisone equivalent.

We also saw evidence of immune reset with complete CD19 positive B-cell depletion followed by emergence of naive B cell repertoire. What excites us the most is the opportunity to potentially redefine the standard of care for lupus patients from a lifetime of chronic immunosuppressants and steroid treatment, which have modest efficacy, cumulative toxicities and a negative impact on their quality of life, to a potential onetime therapy that achieves high rates of immunosuppressant-free clinical remissions.

These data position us exceptionally well with a path for potential approval and a large commercial opportunity ahead. We've aligned with the FDA on a single-arm pivotal study in lupus nephritis, and we plan to initiate start-up activities for the study this coming quarter. Given the high rate of DORIS remission observed in the study, and consistent with regulatory precedent, we expect to expand the single-arm pivotal study to include lupus patients without nephritis.

So stay tuned on that. Our team has established an excellent track record in enrolling lupus patients, and we saw strong interest from both patients and investigators to participate in the clinical study. We believe this positions us well for rapid enrollment of the pivotal study.

Given the generally favorable safety profile observed with prula-cel, we aligned with FDA to enable outpatient dosing of prula-cel. The off-the-shelf availability and scalable manufacturing of prula-cel provides commercial advantages to address the unmet medical need of many patients living with lupus.

Turning to the commercial opportunity. There are approximately 35,000 refractory lupus nephritis patients with organ or life-threatening disease despite currently available therapies and another 35,000 refractory non-renal lupus patients with organ or life-threatening disease who may benefit from a potential therapy like prula-cel.

We delivered on every key objective we wished for in this study, rapid enrollment, a favorable safety profile supporting outpatient dosing and high rates of immunosuppressant-free CRR and DORIS remission. Prula-cel is uniquely suited to potentially make a meaningful difference for lupus patients while generating value for shareholders.

The strength of the data we'll show you today further reinforces our confidence in the prula-cel program and opportunities ahead.

We anticipate a number of meaningful milestones as we continue to advance the program. I'll now pass it over to Lloyd to walk you through the clinical data in more details on the next slide. Lloyd?

Thanks, Chen. Here's a quick review of the trial design. This is a basket study, which includes several autoimmune indications, as you can see on the left, with a dose expansion element, as you can see on the right. We're discussing the lupus cohort with or without nephritis today.

The study periods include informed consent, a screening period, the conditioning regimen, a single dose of prula-cel, a 28-day DLT evaluation period and then patient follow-up.

The primary endpoint was safety and tolerability. Secondary and exploratory endpoints focused on biomarkers of drug activity, including B-cell depletion and reconstitution and immune reset, while the clinical efficacy endpoints were focused on complete responses and remission.

We started enrolling lupus nephritis patients first and subsequently expanded the cohort to enroll lupus patients without nephritis. Let's next look at patient baseline characteristics.

This is a summary of the baseline characteristics of the 16 lupus nephritis and 8 lupus patients without nephritis who were enrolled in the study. You can see the study participants are typical for lupus patients, primarily women with a mean age of 35 who have been living with the disease for years.

These patients had inadequate responses to prior treatment. All had received at least 3 prior therapies and 71% had received 4 or more prior immunosuppressants in addition to glucocorticoids. Their mean baseline SLEDAI score was 13, and those patients with nephritis had a baseline mean urinary protein-creatinine ratio or UPCR of 2.8.

These patient baseline characteristics are similar to other data sets from company-sponsored clinical studies with B-cell depleting autologous cell therapies. This is a summary slide of the CRR rate in the lupus nephritis patients and the DORIS rate in the entire cohort of lupus patients with and without nephritis.

As you can see, the CRR rate reached 50% at month 12 and the DORIS rate reached 54% at month 12. Importantly, these remission rates occurred while patients were immunosuppressant-free and their glucocorticoid dose was 5 milligrams or less of prednisone equivalent.

All 12-month CRR and DORIS remissions are ongoing with a follow-up of 12 to 21 months, except 1 patient with a UPCR of 0.65 grams per gram after month 12, but who continues to remain off immunosuppressants.

Focusing on the 5 patients with a CRR at month 12, 2 of them were already a CRR at month 6. At month 9, they remained in CRR and an additional 2 patients reached CRR. And by month 12, 1 more patient reached CRR. A similar pattern was observed for the DORIS remissions. Those patients who haven't yet reached month 12 are on a clinical trajectory that we expect will be generally consistent with the efficacy we're reporting today.

Notably, in addition to the 50% CRR at month 12, an additional 20% of the nephritis patients had at least a 50% decrease in proteinuria from their baseline levels, which is defined as partial renal response per protocol. As a rheumatologist, the most compelling aspect of these results to me is the potential to change the standard of care for people with lupus.

Currently, these patients are faced with a lifetime of chronic immunosuppressants and steroid treatment, which have modest efficacy, cumulative toxicity and an adverse effect on their quality of life. A onetime therapy that achieves high rates of immunosuppressant-free clinical remissions would be transformative. Let's talk about the safety profile.

Next slide, please. Prula-cel was generally well tolerated and showed a favorable safety profile appropriate for outpatient dosing. Across the 24 safety evaluable patients, there were no dose-limiting toxicities, no immune effector cell HLH-like syndrome or IEC-HS, no ICANS and no CRS events greater than Grade 2.

We have so far enrolled 48 autoimmune disease patients, and this generally favorable safety profile is consistent throughout the entire autoimmune disease program. In this study, Grade 1 or 2 CRS occurred in just 25% of patients.

Of infections that occurred, most were Grade 1 or 2 with Grade 3 in just 2 of the 24 patients. There were no cases of GvHD. We shared our safety data with the FDA and aligned to make prula-cel available going forward for enrollment in the outpatient settings.

When compared to safety data reported for alpha beta CAR-T therapies in autoimmune diseases, we believe prula-cel is generally better tolerated. This favorable safety profile with no IEC-HS, no ICANS at all and no CRS events greater than Grade 2 is consistent with the biology of gamma delta CAR-T cells, which is different from that of alpha beta CAR-T.

So let's now discuss the scientific foundation underlying these findings and why we believe prula-cel's differentiated biology may contribute to its generally favorable safety profile to date. To better understand the promising results, it's important to look at how gamma delta T cells differ from alpha beta CAR-T cells. Adverse events such as IEC-HS, ICANS and high-grade CRS are primarily related to hyperproliferation of T cells and the associated secretion of cytokines, including IL-2 and others that lead to activation of innate immune cells.

These are typically seen with alpha beta T cells. In contrast, our gamma delta T cells secrete fewer and lower levels of these cytokines. In the clinical study, we did not see increase in systemic cytokine levels in prula-cel-treated patients, as you can see on the lower part of this slide.

The differentiated cytokine profile of gamma delta T cells versus alpha beta T cells is consistent also with preclinical data we have published in the past and with third-party publications.

Taken together, the clinical safety findings, the cytokine data and the biological rationale provide a compelling and increasingly consistent picture. Prula-cel may be capable of delivering the benefits of CAR-T-mediated immune reset while mitigating some of the safety concerns associated with alpha beta CAR-T therapies. Let's move to some additional efficacy data on the next slide.

Prula-cel drove a rapid and substantial decline in SLEDAI comparable to the improvement reported with alpha beta autologous CD19 CAR-T therapies.

Importantly, these reductions remain stable to 12 months and beyond, reinforcing the potential for deep and durable disease control. Let's move to the next slide. Prula-cel also drove a rapid and sustained reduction in the Physician Global Assessment, or PGA. 12 out of 22 patients achieved a PGA score below 0.5 at month 6 and 9 and 11 of 13 or 85%, of evaluable patients achieved this threshold at month 12, providing further evidence of sustained disease control.

All patients discontinued their immunosuppressants. So all responses we're discussing today were immunosuppressant-free. 21 of the 22 efficacy evaluable patients have remained off immunosuppressant therapy throughout the study. This suggests that even those patients who have not reached CRR or DORIS are improved such that they do not require immunosuppressant therapy.

In addition, all patients but one tapered their background steroids to 5 milligrams or less of prednisone equivalent. On the next slide, we'll address clinical remission in the overall lupus population with and without nephritis. This slide summarizes the DORIS remission rates for the most recently approved therapies for lupus, which are prescribed on top of other drugs such as mycophenolate or azathioprine plus glucocorticoids. You can see that they failed to achieve high DORIS remission rates despite the ongoing immunosuppressant therapies.

The DORIS rate of 54% observed with prula-cel, shown on the right, is substantially higher than those reported for these other therapies and is qualitatively superior because it was achieved while patients were off immunosuppressants.

Given the strength of the data we've outlined today, we plan to move quickly to advance prula-cel into a pivotal study. Let's discuss the pivotal trial design on the next slide. We initially approached the FDA regarding a pivotal study in lupus nephritis and aligned on a single-arm study in these patients with active disease and inadequate response to at least 2 immunosuppressants.

Subjects must meet the EULAR-ACR 2019 criteria for lupus. The study would be expected to enroll a double-digit number of patients with biopsy-proven proliferative Class III or IV lupus nephritis with or without concomitant Class V involvement.

The primary endpoint would be complete renal response at 12 months. Looking ahead, we plan to discuss with the FDA the expansion of the proposed single-arm study to include lupus patients without nephritis and a DORIS primary endpoint for these patients with a total study size of approximately 90 patients.

In terms of timing, we expect to initiate study start-up activities by the end of the year with interim pivotal data expected in 2028 and a pivotal readout in 2029. Let's discuss unmet need on the next slide. Despite advances in treatment, significant unmet needs remain in lupus. Currently approved therapies fail to achieve durable treatment-free remissions and patients continue to experience disease flares and progressive organ damage, while at the same time, their chronic use of corticosteroids and immunosuppressants can lead to serious side effects.

These challenges highlight the need for a onetime therapy with a favorable safety profile that has the potential to deliver lasting treatment-free remissions. This slide summarizes how prula-cel has the potential to transform the current treatment paradigm for lupus from chronic immunosuppression to a single readily administered therapy that may yield durable treatment-free remission.

If ultimately approved, we believe adoption could be strong for patients, physicians and payers alike. So with that, I'll turn the call over to Blake, who will summarize what we saw in terms of immune reset. Blake?

Thanks, Lloyd. These clinical responses are supported by multiple independent biomarkers that converge on a clear picture of immune reset. Across blood, tissue, serologic and cellular measures, we have observed a consistent pattern of evidence for an immune reset and reduced disease activity.

This reset begins with deep B-cell depletion in every patient who received prula-cel. And in return, these B-cells were renewed by the recovery of a less antigen-experienced B-cell population. Specifically, the reset of the B-cell population was driven primarily by naive and non-class-switched B-cells. Let's take a closer look at the data on the next slide, please.

These data come from the entire set of 22 efficacy evaluable patients. On the left, total B-cell counts show that every patient experienced deep and complete B-cell depletion, all with multiple time points where total B-cells were undetectable in the first month after treatment. This period of deep reset was followed by an orderly reemergence of B-cells within a 1- to 4-month window. On the right, the subtype analysis for these B-cells reveals that this recovery and reemergence is strongly driven by naive and non-class switched B-cells, precisely the less antigen experienced population we want to see here.

The data suggests that with prula-cel, we are effectively giving the B-cell compartment an opportunity for a fresh start. An apparent limitation of antibody approaches in this setting is the inability to effectively deplete these B-cells in tissues. Conversely, a key defining feature of gamma delta T cell biology is their natural propensity for tissue residence. We've observed this consistently across our patient experiences and across our platform over the years, and prula-cel is no exception.

It has also shown deep and complete B-cell depletion in lymph nodes. The example here shows baseline tissue on the left with B-cells shown in green. By day 10, after a single dose of prula-cel, those B-cells in green were completely undetectable and in their place within the secondary lymphoid tissue was activated prula-cel shown in red and yellow.

These effects also extend to key serologic biomarkers. Among patients with evaluable and quantitative data, 90% or more showed reductions in anti-double-stranded DNA titers and concomitant increases in complement reservoirs with approximately 70% returning to the normal range.

This coordinated picture of B-cell reset and serologic improvement aligns directly with the benefits measured by our clinical efficacy endpoints to date, and we believe provides a clear mechanistic foundation for the responses we've observed. Let me now pass it back over to Chen on the next slide.

Thanks, Blake. With those results in mind, let's turn to the patient perspective. Autologous CAR-T can be a challenging journey for both patients and providers. Patients often need to discontinue immunosuppressive therapy weeks prior to leukapheresis to enable harvesting of the T cells with reasonable fitness and then wait for several weeks while their individualized product is manufactured and then released.

During that time, many patients require bridging therapy and treatment is typically limited to specialized centers because of the associated safety risks and monitoring requirements of alpha beta CAR-T. In contrast, the data we've presented today support the potential of prula-cel, if approved, as a readily available therapy that could be administered without leukapheresis or personalized manufacturing.

With immediate availability as an off-the-shelf therapy, a favorable safety profile and the potential to be delivered in community-based settings, we believe prula-cel could offer a substantially simpler and more accessible treatment for patients.

This slide highlights a key point. Not all B-cell depletion modalities are associated with similar clinical activity. In an important study published last year from Erlangen, the investigators demonstrated that protein-based approaches such as bispecifics often result in incomplete depletion of B-cells.

And in the field of [indiscernible] and other autoimmune diseases have not been associated with high rate of clinical responses or remissions, whereas CAR-T therapies have demonstrated more complete depletion of B-cells in tissues and higher rate of clinical responses and immunosuppressant-free remissions.

We believe that distinction is central to the opportunity for prula-cel, which we have observed to provide complete B-cell depletion, immune reset and a high rate of immunosuppressant-free CRR and DORIS remissions.

If complete B-cell depletion is a key driver of clinical efficacy, the next question is where prula-cel fits within the evolving lupus landscape. The next slide highlights our competitive positioning in lupus with and without nephritis.

First, starting on the upper left, autologous alpha beta CAR-T demonstrated high rate of immunosuppressant-free remissions, but are associated with safety challenges such as IEC-HS and ICANS and require leukapheresis and personalized manufacturing.

Moving counter clockwise, bispecifics have shown limited clinical activity compared to autologous CAR-T and will likely require more chronic dosing with associated immunosuppression and all the safety risks that come with it, such as high infection rate. mRNA in vivo CAR-T offers a potentially simpler approach, but as well known with regards to mRNA and as recently published in the New England Journal of Medicine, these resulted in humans in short duration of mRNA expression, short and limited exposure to CAR-T and incomplete B-cell depletion, which is central to the potential efficacy in autoimmune indications.

Lentiviral in vivo CAR-T may provide more sustained expression, though concerns remain around permanent gene therapy, DNA integration-related risks and potential safety concerns due to rapid alpha beta T-cell proliferation. These concerns may make these lentiviral approaches more appropriate for oncology.

Against this backdrop and based on the data presented today, we believe prula-cel is uniquely positioned to address many of the key limitations observed across these approaches.

Prula-cel demonstrated immunosuppression-free remissions comparable with autologous alpha beta CAR-T with a more favorable safety profile. It is a onetime investigational therapy that is off the shelf and is expected to be available in an outpatient setting.

If cell therapy adoption is ultimately driven by efficacy, safety and access, we believe prula-cel is uniquely positioned at the intersection of all 3. This brings us to the market opportunity.

As previously discussed, we believe prula-cel has a significant commercial potential. There are approximately 70,000 patients with organ or life-threatening refractory lupus disease in the U.S. alone. As we advance into pivotal development, we look forward to bringing prula-cel as a much-needed potential therapy for lupus patients.

Beyond prula-cel, we have a broad pipeline of allogeneic gamma delta CAR-T cell therapies and the in vivo CAR-T therapies. Our pipeline is focused on developing these therapies for autoimmune diseases, hematologic malignancies and solid tumors.

As you can see on the slide, with today's data in hand, we've got a significant number of prula-cel milestones that lie ahead. Beyond prula-cel, we're also advancing ADI-212 towards Phase I alongside our differentiated in vivo platform and pipeline targeting hematologic malignancies and solid tumors that are expected to result in additional milestones.

We look forward to providing you additional updates on these programs in the near future. Today's data highlights that prula-cel may provide a meaningful future treatment option for lupus patients and deliver significant short- and long-term value to shareholders.

Thank you for joining us today. With that, let's open up the call for Q&A.

[Operator Instructions] Our first question comes from Dennis Ding with Jefferies.

On the phenomenal data. So I have 2 questions. Number one, on the platform. I'm just curious if you've had any kind of potential discussions with pharma over the last 6 to 12 months and what we're seeing with alpha beta T-cells and their potential safety liabilities. Do you think pharma and maybe even also the broader industry are starting to appreciate that gamma delta T-cells have a different risk reward? Or do you think the platform needs to be further derisked with pivotal data? And then question number two is just on the interim. Just how are you thinking about the different scenarios you're thinking about for that interim and how would the stats work given the pivotal will be a single-arm trial?

Dennis, thank you for 2 good questions. So I'll start with the first one and perhaps Lloyd can jump in with regards to the second one. We certainly have seen overall an increase in the interest in the platform and in prula-cel since the liabilities with the alpha beta T-cells has been presented, primarily in the autoimmune field. Unlike in oncology, where maybe this risk benefit is reasonable in autoimmune field, I believe that patients don't want to take the risk on IEC-HS. It has been presented as we've seen in 2 cases with rapid manufacturing.

But generally, there are concerns that this will be presented with regards to alpha beta T-cells in general because you never know who is the patient that has great T-cell fitness and might hyperproliferate and eventually lead to this IEC-HS. So one of the key benefits indeed that we see with our platform is this very, very favorable safety profile that is really appropriate for autoimmune diseases, and combined with the efficacy that we've seen, I think we are in a sweet spot.

So to summarize the answer to your question, we certainly see an increase in the interest generally from pharma companies. Obviously, we don't want to comment on any specific discussions, but that's certainly something that we expect to be helpful. Your second question, I believe, was regarding the potential plan for -- we do plan for interim analysis. So Lloyd, perhaps you can address the second question.

Sure. Thanks, Chen. So the details of the study design are not finalized yet. We have an upcoming meeting with regulators on this topic. We have competing issues with the interim analysis, of course.

We don't want to spend alpha. We don't want to increase the study size and increase the duration, while at the same time, we'd like to generate some confidence building data early in the study. So we're working through that. And as soon as we have it finalized, we'll disclose it.

I might add one point here, Dennis. What's nice about the plan for the pivotal study, essentially, it's the same patient population, and they're refractory to at least 2 immunosuppressants.

In our case, as you've seen, all the patients were refractory to 3 immunosuppressants and about 70% of them were refractory to 4. So it might be quite easy to enroll these patients, and there's really no difference from the patient population that we enrolled in the study. So we're confident in the probability of success, and we're even more confident in our ability to enroll the study quite quickly. Thank you for both questions.

Our next question comes from Yatin Suneja with Guggenheim.

Can you hear me?

Yes.

Congratulations on very good data and updates. Maybe just a couple for me. The first one is with regard to the lupus nephritis. Could you just talk about -- I understand you're going to do one study, a single-arm study.

Maybe if you can put some numbers around how big that study might look like, how many patients that could be? So that's number one. And the second question is regarding the CRR rate that you're seeing at 12 months. Obviously, you have a lot more patients moving in from 9 months to 12 months, let's say, in the next 3 to 6 months time frame.

How should we think about -- what is the trajectory of responses you are seeing in those 6 patients that are going to move from 9 to 12? Just trying to get a sense that once you have, let's say, all 16 patients out to 12 months, how should we think about the response rate? And then what about the durability of responses? Like anything you can comment on because you should have patients that have more than a year of follow-up.

Sure. So let me -- I wrote your question. Let me address the first one and then perhaps Lloyd can address the second one. Well, in lupus nephritis, essentially, we would expect our endpoint to be immunosuppressant-free complete renal response. There's actually no drug out there that provides immunosuppressant-free complete renal response.

So your comparator is essentially 0. If you look at the examples of pivotal studies that have been started by 2 other companies, there's 2 examples. I wouldn't -- I'm not going to mention the specific names of the companies. They're available on clinicaltrials.gov.

But these pivotal studies are in the range of, again, single-arm studies in lupus nephritis patients and the number of patients is in the range of 35 patients to 50 patients. And if you look at the clinical studies that include both LN and SLE, then again, these examples are in clinical trials.

So there's one example when it's 89 patients, and there's a different company that initially started for some reason, a randomized study and then changed to a single arm. And in their case, it's 179 patients. And we think it's just because they started in a different way. So bottom line, single -- double-digit number of patients, whether it's LN or LN and SLE. And I think given our enrollment track record, we can enroll it quite quickly. Now regarding your questions on CRR, I think I'll divide it to 2. One of them was what can we comment on the durability beyond 12 months? And the second one, I guess, is what do we see in the patients at 9 months and what's the trajectory. So perhaps, Lloyd, you can address these questions.

Sure. Thanks. So first question was durability of response. We'll start at the back and move up. So for the 12-month CRRs, all of them have remained in CRR, except for one whose urine protein-creatinine ratio has bumped up a [ tad ] to 0.65 grams per gram, but the patient remains well on off immunosuppressants.

For the second part of your question was what about the patients who have not yet reached month 12, and we have 6 of them at 9 months. And of those, they are on a trajectory that we do not expect is going to change overall the rate of response we see at 12 months.

The next question comes from John Newman with Canaccord Genuity.

I'm just curious, did you have any patients in the trial that were previously exposed to other CD20 targeting therapies? You had a nice slide discussing how you think the mechanism of action for gamma delta T-cells is more effective there. Just curious if there were patients in the study that had previously been exposed to other CD20 therapies. And if so, how those patients are doing?

Yes. Maybe I'll take that one, Chen. So we did have a few patients who had received rituximab in the past. And it didn't have any effect on the responsiveness to our therapy. I think the most likely reason is you saw from some data that Chen showed that antibody therapeutics don't effectively deplete B-cells in tissues. So the pathogenic B-cells are unlikely to have been adequately exposed to rituximab. So it didn't have any effect on the efficacy of our therapy.

Great. And if I could ask one additional question to Dr. Klickstein and Chen. When we're talking about late-stage lupus nephritis patients, I'm wondering if you could discuss just briefly the risk of severe kidney damage or eventually dialysis or something worse. And could you talk about potentially how prula-cel perhaps could help prevent some of these cases in the future?

Yes. So progression of lupus nephritis is well documented and not infrequent. And we believe that effective therapeutic intervention will prevent these patients from moving forward.

There have been studies in lupus nephritis patients that show if you can put them into remission and have that be maintained for 12 months, then the likelihood of progression is very low. So we're very optimistic about this, but we have to accumulate more data before we can make a statement regarding prula-cel in that regard.

The next question comes from Robert Driscoll with Wedbush.

Adding my congratulations here for the data. Maybe just a question on dose for the pivotal study and how you're thinking about kind of integrating all the data here for that discussion with the FDA? And then maybe just a quick question for Blake around T-cell recovery and the kinetics of that. What does that tell you about the durability of the gamma delta T-cells and what might be optimal here with the treatment?

Sure. Absolutely. So Lloyd, why don't you start with the first one and then Blake, you can do the second one.

Yes. So regarding the dose, in the data you've seen today, we had 4 patients on 1E8, 3 patients on 10E8 and -- I'm sorry, 10 patients on 3E8 and 10 patients on 1E9. And we did not see an efficacy dose response. We did see a ramping up of exposure as a function of dose.

And just as a reminder, these doses reflect total CAR-T positive T-cells infused. And safety-wise, there was a trend towards increased events at the highest dose of 1E9. So integrating the total efficacy, safety and biomarker data packages, we've selected 3E8 as the dose that we're going to propose for the pivotal study. Of course, we have to discuss this and get agreement from regulators. Blake, do you want to do the B-cell recovery part of the question?

Yes, absolutely.

Thanks, Blake.

As Lloyd just mentioned, right, the integration of all of our biomarkers inform our dose selection. On the B-cell depletion, every patient on every cohort that's reported here received a single dose of prula-cel and achieved maximal depletion of B-cells as detected in the blood.

That recovery time occurred generally between 1 month and 4 months. So it's after that initial 30 days is when we start to see that recovery, again, driven by those naive and less antigen-experienced B-cells, which is a great observation. That recovery period is quite nominal. That's what we see across autologous CAR-T therapy.

So we don't see any difference really in the recovery kinetics of those B-cells from what others have reported, whether they're autologous or other.

And again, this is a single dose. We really haven't seen any instances where we really want to start talking about a second dose at this point. This really does seem like a one and done at this point, at least up to the data points that we're showing here at 12 months.

Our next question comes from Boris Peaker with JonesTrading.

I'd like to add my congratulations on the data. I'm just curious, kind of expanding on prior questions. Are there factors around the B-cell reset, maybe like the duration of B-cell being undetectable or other biomarkers that correlate with efficacy? Maybe in other words, any specific biomarker that you could identify the responders and nonresponders during the depletion phase?

Blake, why don't you try that one?

Yes, absolutely. Again, I think our strongest biomarker here right now is the depletion period in that first 28 days. We see multiple time points within that 28-day window where those patients have undetectable B-cells, CD19 positive B-cells, I'll remind you, in the blood.

Honestly, that's really a key biomarker here. And again, that recovery of the naive B-cell phenotype is promising to see as those are characterized as being less antigen experienced.

Yes. Boris, I would add one more point, just to step back and you think about the patient benefit. So in the LN, you see 50% achieved complete renal response, 20% achieved partial renal response.

When you look at lupus with and without nephritis, you see 54% at DORIS but all those patients that maybe did not show a remission or partial renal response, you see that the SLEDAI went down, the PGA went down and 21 out of the 22 patients didn't need to take any immunosuppressants.

So essentially, almost all the patients in this study benefited from prula-cel. So we find it very, very encouraging for these patients.

Now I guess my question was, is it plausible that maybe some patients need a longer B-cell depletion to achieve a response and just assessing it by a peripheral depletion that may be difficult to just measure from a blood test?

Yes. I would say the field, and if Blake and Lloyd has something to add, they can definitely add. I would say in the field, the key is immune reset.

If you see immune reset, then you can hope for good clinical outcomes, and we have seen this immune reset.

I would just say that we do like the B-cell depletion because it's a very robust pharmacodynamic biomarker. The totality of the evidence also inform us here, again, 90% and 91% of the evaluable patients that received prula-cel also showed improvements in double-stranded DNA titer and complement reservoirs, right? So these are all factoring into the activity of prula-cel and what we're reporting here.

Again, the disease benefit and the disease activity is quite substantial here despite the 50%, 54% DORIS, which in and of itself is quite amazing, especially that those are drug-free remissions.

Our final question today comes from Robert Burns with H.C. Wainwright.

Just 2, if I may, here real quickly. So I know you're going to be talking with the FDA later this year. Are you guys going to announce an update with regard to the results of that discussion later this year? And then maybe just on immunosuppressants, help frame how important it is that these patients didn't have concurrent immunosuppressant usage relative to what we've seen with other players in this field and whether concurrent immunosuppressant usage has a meaningful impact on complete renal response rate?

Sure. I can start with the first one and maybe give some background to the second question and Lloyd can address. So regarding the FDA, we do expect to meet with the FDA in the fourth quarter and discuss the final design of the lupus nephritis study and the potential expansion to SLE.

We haven't guided, but I would expect that we will update investors once everything was finalized and settled. Regarding the second question, just to give some background, there was one example by one big pharma that shared data in 21 patients with SLE with and without nephritis. Their data in terms of efficacy was reasonable, quite comparable to us.

And that pharma put their study on clinical hold. But what was shared by the big pharma is that 8 out of the 21 patients have been taking immunosuppressants during the study. And in our case, as you've heard, 21 out of the 22 did not take any immunosuppressants, only 1 patient started taking immunosuppressants. So Lloyd, I think the question was, did the immunosuppressants in either case help their efficacy potentially?

Yes. So let me address that. I heard 2 questions. One is, did they contribute to efficacy? And the answer is probably. The second part of the question was why are -- why is being immunosuppressant-free important? And perhaps the best objective example of that is the recent obinutuzumab study in lupus that was published in the New England Journal, where patients, of course, were all on immunosuppressant therapy, obinutuzumab plus mycophenolate or azathioprine and steroids.

The infection rate in that study was substantial, around 70%, as I recall. So ongoing and chronic use of immunosuppressants has a lot of morbidity associated with it plus the cost and everything else.

There are no further questions at this time. This concludes today's call. Thank you all for joining. You may now disconnect.

Hello, everyone, and welcome to the Adicet webcast. [Operator Instructions]. This call is being recorded.

I'll now turn the call over to Chen Schor, CEO of Adicet Bio. Please go ahead.

Good morning, everyone, and welcome to today's conference call to discuss the data we announced this morning from our ongoing Phase I study of ADI-001 demonstrating very promising safety and efficacy results in patients with LN and SLE.

I'll start the presentation with a few remarks before turning it over to Dr. Julie Maltzman, our Chief Medical Officer, who will summarize the clinical data to date. After that, we'll be joined by Dr. Blake Aftab, our Chief Scientific Officer, to walk us through the data demonstrating clear evidence immune reset that we observed in the study. And then Nick Harvey, our Chief Financial Officer, will join us for Q&A. Next slide, please.

Before we start, please note that today's call may include forward-looking statements based on our current expectations. These statements represent our judgment as of today and inherently involve risks and uncertainties that may cause actual results to differ materially from the results discussed. Please refer to our filings with the Securities and Exchange Commission for more information.

And now without further delay, let's get started. We're excited to share with you that the key takeaway from the Phase I study we are sharing today points to potentially unequivocal success for patients with autoimmune diseases and for treating physicians.

We believe this data set highlights the potential of ADI-001 to become a transformational paradigm-changing approach to treating patients with autoimmune diseases. These preliminary data checked all the boxes in terms of the efficacy and safety results that we had hoped to see at this stage.

Let's take a moment to revisit our aspiration for this trial. Previously, we laid out what good readout from the trial would be. First, we said that the data would hopefully demonstrate favorable safety profile suitable for outpatient administration. We clearly have that, with no SAEs, no CRS events greater than Grade 1 and no ICANS. We believe this lays the groundwork for ADI-001, potential advantage of being used as an outpatient therapy and available to many patients with autoimmune diseases.

We also said we wanted to achieve remission or halt disease progression. And we did, as you will see in the clinical data we present today. All patients, which includes five LN patients and two SLE patients with a follow-up ranging from 2 to 9 months experienced rapid and sustained reductions in their SLEDAI-2K and Physician Global Assessment or PGA scores.

Next, we wanted to show preserved or immune kidney function with a complete renal response or CRR rate of at least 40%, which is what regulatory authorities signaled to other companies as the bar for success in single-arm pivotal studies with B-cell depleting cell therapies for the treatment of LN. And indeed, kidney function improved in all five LN patients, including three complete renal responses, which were also DORIS remissions and two partial renal responses. We also wanted to see immune reset and emergence of B-cell repertoire that will support a onetime therapy, and we clearly did, which Blake will present shortly.

We hope to see a discontinuation of immunosuppressants and discontinuation or reduction in the corticosteroid doses to physiological levels. That box was clearly checked.

Finally, we wanted to see the potential for ADI-001 to become an off-the-shelf therapy with no need for leukapheresis, and we have that as well.

In summary, with all these boxes checked, today's data are a clear win for LN and SLE patients. These data exceeded our expectations. The totality of the data suggests that ADI-001 has the potential to be an off-the-shelf onetime therapy available for autoimmune patients in an outpatient setting with an impressive efficacy profile and favorable safety. Such a profile may enable rapid execution of our clinical development plan and if ADI-001 is approved, significant commercial potential.

Given the data we're presenting today, we plan to request a meeting with the U.S. Food and Drug Administration, or FDA, in the first quarter of next year, to inform Phase II pivotal trial design with a study anticipated to commence in the second quarter of next year.

Precedent Phase II pivotal trials with B-cell targeted cell therapies in LN or SLE and LN suggests that a relatively small single-arm pivotal study may suffice given the transformational clinical benefits observed with immune resetting cell therapies. Next slide, please.

The autoimmune program with ADI-001 is quite robust. We have seen a nice uptick in the number of sites interested in enrolling patients. We continue to enroll LN and SLE patients and recently also started enrolling systemic cirrhosis patients. We expect to enroll patients with RA in the very near future and also see interest from sites in enrolling patients with myositis and ANCA vasculitis.

ADI-212, our optimized next-generation gene-edited and armored clinical candidates designed to enhance potency in solid tumors and deliver multiple antitumor mechanism of action to the tumor microenvironment, ADI-212 is expected to enter the clinic in the first half of 2026. But today, we'll be focusing on the data from our Phase I trial in LN and SLE. Next slide, please.

Given the strength of the data we are sharing with you today, we expect our ADI-001 program to generate a number of meaningful milestones throughout 2026. We will review these milestones in more detail shortly.

With that, let me now turn the call to Julie to walk you through the clinical data in more details on the next slide.

Okay. Thank you, Chen. Good morning, everyone, and thank you for joining us. I am pleased to be here today to share these preliminary results from the Phase I study of ADI-001 in patients with LN, Lupus Nephritis; and SLE, Systemic Lupus Erythematosus.

This slide here just summarizes the data that I'll be showing you today. It includes seven patients in total, five LN and two SLE as of August 31 data cut.

I'm very pleased to report that we saw a rapid and sustained reduction in the SLEDAI-2K and PGA scores across all patients. You will also see that all LN patients had a reduction in proteinuria. Three patients achieved a complete renal response or CRR. These same three patients also achieved DORIS remission. The other two patients fit the protocol definition of a partial renal response or PRR, which is defined as a drop in proteinuria by greater than 50% from baseline.

ADI-001 was very well tolerated with no CRS greater than Grade 1, no ICANS and only one Grade 1 infection. There was clear evidence of an immune reset that Blake will walk you through in a bit. And all patients discontinued immunosuppressants and tapered steroids to zero or below 5 milli equivalents of prednisone daily.

So next slide, please. In the interest of time, I'm not going to go into great detail on this slide other than to remind you that there is a major unmet medical need for LN and SLE. Most patients get treated with chronic triple therapy that is two immunosuppressants and a steroid. More recently, there is even a suggestion of adding on a biologic treatment. All these therapies carry significant toxicities in these young patients. There is a clear need for a onetime therapy with a favorable safety profile that can deliver flare-free remissions without the need for these chronic therapies.

Next slide, please. Here's a quick review of our trial design. This is a Phase I study with a 3+3 basket design, which includes several autoimmune indications that you can see on the bottom left of this slide and then a dose expansion that is indicated on the bottom right. The patient's journey begins with signing consent, a screening period, conditioning regimen, cell infusion, a 28-day DLT dose-limiting toxicity evaluation period and then follow up. Patients are considered enrolled when they start conditioning.

Next slide, please. Primary endpoints for Phase I studies are always safety and tolerability, and our study is no exception. Secondary and exploratory endpoints focus on pharmacodynamic endpoints, including B-cell depletion, reconstitution and immune reset and the clinical efficacy endpoints are specific to each disease as outlined on the bottom right of this slide.

Next slide, please. Well, this is the baseline characteristics of all five LN patients and two SLE. They have follow-up ranging from 2 to 9 months, you can see they're primarily young women that have been living with their disease for quite some time, ranging from 2 to 22 years, and this reflects the typical demographics for SLE and LN.

Their baseline SLEDAI scores were in the mid-teens, and all LN patients had over 1.5 grams of protein in their urine. Patients had anywhere from three to seven prior therapies, and overall, these patient baseline characteristics are consistent with other data sets from company-sponsored clinical trials with B-cell depleting autologous cell therapies.

Let's go to the next slide, please.

So let's look at safety. ADI-001 was extremely well tolerated in these patients with no SAEs reported, no ICANS, and no CRS events greater than Grade 1. We had two patients with Grade 1 CRS, which, of course, is defined by the American Society of Transplantation and Cellular Therapy as a fever of over 38 degrees centigrade, which is about 100.4 degrees Fahrenheit. We also had one patient with a Grade 1 upper respiratory tract infection that happened about 3 months after cell infusion and resolved quickly without the need for antibiotics. Most notably, we did not have any neurotoxicity, no ICANS, no HLH, no GvHD.

Let's go to the next slide to see how ADI-001 data compares to other therapies in development.

So you could see in the blue box on the left, ADI-001 safety profile compares favorably with autologous alpha-beta CAR-T therapies in autoimmune patients. We believe this profile gives us the potential opportunity to dose ADI-001, as an off-the-shelf product in the outpatient setting. We were so encouraged by these results that we plan to speak to the FDA to see if we could administer ADI-001 as an outpatient therapy in clinical trials going forward. This would be a huge win for patients in our studies. And if approved, it will eliminate a major burden on the healthcare system by making this therapy more readily available. So please stay tuned for more information on that.

Let's move on to the next slide, please.

This slide shows the efficacy data for our LN patients specifically. You could see all five LN patients that received ADI-001, achieved a renal response. That's a wonderful outcome. In the bright blue, you can see three complete renal responses and DORIS remissions for patients LN1, LN4 and LN5. Two LN patients achieved a partial renal response, which is defined per protocol as a drop in proteinuria by more than 50% from baseline.

As far as we know, all these responses are ongoing at this time. We're also pleased to observe that the complete renal response rate shown here exceeds 40%. 40% is what regulatory authorities have signaled to other companies as a bar for success for a single-arm pivotal study for cell therapies in lupus nephritis.

Let's go to the next slide, please.

Well, this is a summary of all the SLEDAI-2000 -- SLEDAI-2K scores for all patients. We're extremely pleased to see that patients had a brisk and durable reduction in their symptoms as defined by the SLEDAI. You can see SLEDAI scores from these patients start out in the mid-teens and have a nice decline.

If you draw your attention to the orange triangle on LN1, LN4 and LN5, these are the patients that achieved a complete renal response and are also in a DORIS remission. The asterisk on this slide highlights three patients that were missing biomarker data, either anti double-strand DNA antibodies or complement levels at these particular visits. So we just assumed that they were positive to show the most conservative data for the SLEDAI-2K.

All right. Next slide, please.

This shows the PGA scores. This slide shows a rapid and sustained reduction in the Physician Global Assessment, or PGA, across all patients, which further highlights ADI-001's impact on overall disease activity. The bright blue line that you see represents the mean PGA for all patients. If you draw your attention for a moment for this orange line, mustard color, you will see the data for patient SLE-2. You could see that their PGA score decreased from 2 to 0.6 by month 3.

On the last slide, I showed you that the same SLE-2 patient had a clinical SLEDAI score of 0. So it's kind of important to highlight that this patient missed the DORIS remission cutoff by 0.1. And we're anxiously awaiting for this patient's next visit to see if they become a DORIS remission if all continues.

Next slide, please.

All patients discontinued immunosuppressants. And you see on this slide that all patients tapered their steroid use to zero or below physiologic levels, which is considered 5 milli equivalents of prednisone daily. Four of seven patients discontinued all steroids, and the remaining three tapered their steroids to 5 milli equivalent or less of pred. This is a tremendous result for patients given that current therapy includes chronic treatment with immunosuppressants and steroids that are associated with significant toxicity.

Long-term corticosteroid use, of course, leads to cataracts, diabetes, bone loss, easy bleeding, not to mention psychological issues. These treatments negatively impact quality of life for patients and their ability to live independent lives.

In summary, we're very excited with this data set. Patients want a single treatment with minimal side effects that could lead to disease remission and prevention of organ damage. We will continue to follow these patients enroll additional LN and SLE patients on the study and of course, advanced enrollment in all other cohorts.

And with that, I'm going to turn it over to Blake to summarize the data in immune reset. Blake?

Thanks, Julie. Let's go to the next slide, please. These robust clinical responses are particularly compelling and are further supported by biomarker evidence of an immune reset. We see multiple levels of evidence supporting this reset. With the loss of B-cell clones presenting at baseline and the emergence of a new less antigen-experienced B-cell repertoire. Specifically, we saw evidence of deep and broad B-cell depletion. That is the first step in a reset. Then we saw reconstitution driven primarily by naive and non-class switched B-cells.

At the genetic level, we also observed depletion of clonally dominant and potentially pathogenic B-cell receptor clones. This was followed by the emergence of a new B-cell repertoire associated with previously undetected antigen receptor sequences. So we've checked the box here on all of these.

Let's now go to the data and take a closer look. Next slide, please.

Looking generally at B-cell depletion, we can see that every patient experienced a deep and broad B-cell depletion, all with multiple time points where B cells were undetectable in the first month after treatment. This initial period of deep depletion was followed by reemergence of B cells within a 1- to 4-month window. This is very much in line with the dynamic seen with autologous CD19 CAR-Ts. With ADI-001, we are clearing the field and allowing new graphs to grow.

Next slide.

This slide provides an initial look at what these shoots are like with respect to B-cell phenotype and the degree of antigen experience associated with those B cells. Here, we show the spectrum of B-cell experience and maturation ordered from left to right, starting with the less antigen-experienced naive B-cell on the left and running through the most antigen experienced plasmablasts on the far right.

Here, we see that the reconstitution of B cells was primarily driven by naive, transitional, and non-class switched B cells, which is exactly what we want to see. And this is again in line with what has been previously seen with autologous CD19 CAR-Ts. These data are consistent with the current level of definition of an immune reset as reported by others. However, this doesn't objectively tell us about how these B cells are engaging with their antigens. To get a more objective view of this, we turn to deep sequencing of B-cell receptors which is how these cells recognize and engage auto-antigens.

Let's go to the next slide.

This slide shows our insights from deep sequencing in three patients from whom samples are available and demonstrate that dominant B-cell receptor clones that were seen at baseline were broadly eliminated after treatment with ADI-001, and were largely not detectable in reemerging B cells. Sorted from top to bottom are dominant B-cell clones, each expressing a unique B-cell receptor and the relative abundance of these clones is depicted by the depth of color.

In the right column for each of these patients, we see that these clones were broadly eliminated in B cells that reemerge at the 6-month and 3-month time points following treatment with ADI-001. Using deep sequencing, we can see that we are clearing the field and initiating an immune reset at the B-cell receptor level at the level where these cells engage with antigens. We can use this same analysis to evaluate whether the grass that grows in its place is in fact new.

Let's go to that in the next slide.

Here, we expand the view of it, looking again at the dominant B-cell receptor seen at baseline, now shown in pink for each of these patients. Following these tracks, we can see that these were largely eliminated and no longer detectable in B cells reemerging following treatment with ADI-001.

Similarly, in blue, we have highlighted B-cell receptor sequences that were not detected or present at baseline. We can see that these patients' B-cell repertoires are largely repopulating with completely novel B-cell receptor sequences, suggesting that these patients have experienced an immune reset at the antigen receptor level, representing a new B-cell repertoire. This depth of view for the immune reset is very much a story of out with the old and in with the new.

Let me pass it back to Chen.

Thanks, Blake. Next slide, please. This slide shows the sustained reductions in SLEDAI scores across industry-sponsored clinical trials with autologous CD19 alpha-beta cell therapies.

As you can appreciate, the sustained reduction in SLEDAI with ADI-001, is overall consistent with these data. Importantly, obe-cel on the top right observed three CRRs out of six LN patients or a 50% complete renal response rate. Rap-cel on the top middle chart presented a very robust data set at EULAR just a few months ago. The data set included 12 LM patients and nine SLE patients. And on the next slide, we can see the percentage of patients that resolved that proteinuria.

Next slide, please.

As you can see on the top right of this slide, the percent of patients with proteinuria dropped from approximately 70% at screening to 35% by month 12, suggesting approximately a 50% complete renal response rate. So we have two examples of company-sponsored clinical studies with autologous CD19 alpha-beta CAR-T in LN patients demonstrating an approximately 50% complete renal response rate. And these data are very consistent with the CRR rate we are observing with ADI-001. ADI-001 has the advantage of being off the shelf and generally well tolerated, hence potentially optimal for dosing in an outpatient setting.

Next slide, please. As Julie mentioned earlier, regulatory authorities have signaled to other companies that the bar for success in single-arm pivotal studies with cell therapies in LN is a complete renal response rate of 40%. This slide shows the pivotal studies underway in LN and SLE and LN with autologous CD19 alpha-beta CAR-T product candidates.

Let's go to the next slide. There are two key takeaways from the data we presented today. One, this clinical data supports the potential of ADI-001, as an off-the-shelf immune resetting, onetime, well-tolerated therapy that could be used in the outpatient setting. And two, we believe that a product candidate with this product profile could enable treating physicians to provide patients with LN or SLE with a potential of onetime therapy that leads to disease remission or how disease progression, while patients discontinue the use of chronic immunosuppressants and reduce the dose of corticosteroids to zero or below physiological levels. This could be a transformational treatment for many patients with autoimmune diseases.

Next slide, please. We have now activated over 25 clinical sites globally, which is a testament to our team's focus and excellent execution as well as demonstrating investigators' interest in ADI-001. The pace of enrollment, we are now observing reinforces our confidence in our timelines for future milestones.

Next slide, please. We believe there is a significant market opportunity in front of us and that ADI-001 has the potential to change clinical practice across multiple autoimmune indications. In addition to the six indications we already have underway in our Phase I program, we have recently opened enrollment for a new Phase I study for the treatment of RA. This trial will explore the use of ADI-001, following Cy/Flu versus Cy only conditioning. With these trials underway, we are poised for a number of milestones in 2026, as outlined on the next slide.

We plan to request a meeting with the FDA in the first quarter of 2026 to inform Phase II pivotal trial design in LN or in LN and SLE, with the study anticipated to commence in the second quarter of 2026. Precedent Phase II pivotal trials with B-cell targeted cell therapies suggest that the relatively small single-arm pivotal study may suffice given the transformational clinical benefits observed with immune resetting cell therapies. Stay tuned for these updates. SLE and LN patient enrollment to the ongoing Phase I is expected to continue until the Phase II pivotal study is open for enrollment. The Phase I program is now open for enrollment of patients with Systemic Cirrhosis, Myositis, Stiff Person syndrome, ANCA vasculitis, and RA. We expect 2026 to be a year with many meaningful milestones.

In the first half of 2026, we expect the following milestones. A clinical update in SLE and LN with more patients enrolled to our Phase I study and longer follow-up. We expect to announce alignment with the FDA on the pivotal study design in LN or in LN and SLE. We expect to announce the initiation of a pivotal study in LN or LN and SLE. We expect a clinical update in systemic sclerosis and a potential clinical update in other autoimmune indications.

In the second half of 2026, we expect to provide the following milestones. A clinical update in SLE and LN, a clinical update in systemic cirrhosis, clinical data from our study in RA, that we recently opened for enrollment, and a potential clinical update in other autoimmune indications. We also have an ongoing program with ADI-212 in metastatic prostate cancer. We plan to file an IND for the program in the first quarter and clinical clinical data potentially in the second half of next year.

With that, let's open the call for Q&A. Operator?

[Operator Instructions] Our first question will come from Jenna Li with Jefferies.

This is Jenna joining for Clara at Jefferies. Congrats on this data. We have two questions, if we may. The first one is, can you help us understand if there were any notable trend in LN2 and LN3, both of which had complete B-cell depletion. Are you observing anything that could suggest they may advance towards complete remission with longer follow-up? And specifically on the SLEDAI chart, I noticed that for both of these patients, the last month had a start on it, and it looks like there were some unavailable samples and some assumptions. If you could just elaborate on that and how that could change or evolve over time?

Sure. Let me start and then perhaps Julie can add. So first of all, what success looks like, if we -- in 50% of the patients, if we can see a complete renal response and they stop taking their immunosuppressants and reduce corticosteroids to zero or below 5 milli equivalent of prednisone, that's a huge win. Keep in mind that otherwise, these patients will continue to be immunosuppressed and tend to die in their 50s from kidney failure. So that's a big, big win.

Regarding the question of LN2 and LN3, Julie, perhaps you can share some background. I think patient 2 had many years of disease, if I recall.

Yes. And thank you. That is correct. Patient 2 had disease for 22 years. She's our longest duration. These two patients are the ones that had a partial renal response, that decreased their proteinuria by greater than 50%. As Chen said, this is still a major win for them that they're off immunosuppressants and off steroids or nearly off steroids with less than 5 milli equivalents.

And you had in the -- there was a second question. Can you remind us what was the second question?

Asterisk. Yes, essentially -- so for example, LN2 and LN3, we just wanted to get you guys there best update as of August 31. So for example, for LN2 and LN3, we brought them to unscheduled visit. And in that unscheduled visits, we got their clinical fleet, but we didn't have the sample to analyze for dsDNA or for C3 and C4. So we just assume they're positive for the most conservative view of the SLEDAI-2K score.

Okay. Got it. And if I may, how would this data inform your thinking on next steps? Potential design for registrational patient selection, baseline, dose, et cetera.

Yes, absolutely. They say, the work of the holy ones is done by others. So first of all, other companies like BMS or Autolus or Novartis have moved to potentially pivotal studies after data sets along the number of patients that we provided, the same duration of follow-up. What we know based -- there was a slide here in the deck. What we know is that these studies tend to be single arm, number of patients in the 30 to 90 patients, and the endpoint is a complete renal response and the bar is at least 40%.

So what's the design? It's kind of out there and we expect to follow what the others have established in the field. The only question that we have is the pivotal design in LN or in LN and SLE or maybe start with an LN and then expand to an LN and SLE, and we'll discuss this with the FDA in the first quarter of next year.

In the interest of time, please limit to one question. Our next question will come from Yatin Suneja with Guggenheim.

Perfect. Julie and Chen, thank you so much for the presentation. Excellent results here. Obviously, very impressive in terms of both efficacy and safety. So the question I have is around durability. Could you maybe talk about your view on the durability? How should we think about that, maybe contextualize some of the immune reset results that you are seeing in that regard? So that's sort of first question.

And then the second, which is a quick question is, could you just let us know what was the lymphodepletion doses that you use? Was it similar to what we are seeing with other CAR-T auto designs?

Sure, absolutely. We're very happy with the durability. What's nice to see is generally immune resetting therapies show very nice durability. So as you can see, just as an example, LN1 had a complete trailer response at month 1 and has a follow-up of 9 months. Generally, all the patients as of August 31, we've seen very nice responses. I can confirm to you that as of now, we're not aware of any relapse. And if we're aware of anything, then patients continue to improve. So we're very, very happy with what we're seeing here.

The data in terms of the number of patients and follow-up of patients is completely consistent with what autologous cell therapy companies had before they started their pivotal studies.

So that was one question, and you had another question, lymphodepletion. The lymphodepletion regimen here is very consistent with autologous cell therapies that are going into pivotal studies. There is nothing unique about it.

Our next question will come from Asthika Goonewardene with Truist.

This is Karina for Asthika. Congrats on the data. I guess, you mentioned like on baseline characteristics, but how would you compare the baselines to other LN trials? And I guess more specifically, is it more similar to George Schett's baseline characteristics?

Absolutely. First of all, thank you for asking. What we're not comparing, we're not comparing to baseline characteristics of a ISTs. What we are comparing is generally to baseline characteristics of other company-sponsored studies. But even if compared to Schett, it might be the same.

Overall, when you look at the age, it's approximately the same. If you look at the duration of disease, 2 to 22 years is very much the same. If you look at the SLEDAI score, our mean was 14. If you look at Novartis, which is the largest industry-sponsored study that was presented so far, their mean SLEDAI at screening was, guess what, 14. If you look at the UPCR, above 1.5. This is definitely an LN patient. We confirmed all LN patients with a recent biopsy. If you look at the number of prior line of therapies, 3 to 7 is very consistent with other studies.

And if you look at the corticosteroid levels, they all were on steroids. So bottom line, if you compare our data set to the data set presented by small companies like BMS or Novartis, and also Autolus very consistent with their data set. If you look at our SLEDAI reduction, very consistent. If you look at the baseline characteristics, very consistent. And if you look at the complete renal response very consistent. So we're very happy with this data.

Okay. That's helpful. And I guess another one is regarding pivotal study. Would this potentially be single-arm similar to obe-cel and BMS? Or how are you thinking about the pivotal design?

Again, can you repeat the question? I just want to make I understand it.

Yes. On the pivotal design, are you thinking about doing potentially a single-arm study similar to Autolus and BMS? Or how are you thinking about the design?

Yes, absolutely. So we know that the clinical benefit that we see with these studies are so transformational that the pivotal study this year are expected to be single arm, relatively small with an endpoint that's relatively short in the 6-month range and the endpoint is complete real response or it might be, in some cases, it might be dose remission if it includes SLE. Yes, absolutely. We expect relatively small single-arm pivotal study, and we'll discuss this with the FDA in the first quarter of next year and hopefully start the study in the second quarter.

Absolutely. The range is approximately 30 to 90 patients based on what we've seen from other companies.

Our next question will come from John Newman with Canaccord Genuity.

Congrats on the tremendous amount of hard work that you guys have put in to this study and all the programs. This is a really great day for lupus patients and autoimmune patients. Just had two quick questions. So just following on to one of the earlier questions, we saw with Novartis' data for rapcabtagene, they saw a very rapid decline in a lot of the SLEDAI-2K items, including proteinuria. And importantly, that proteinuria, even though it didn't go to zero, it continued to drop over time. So my question is, is it reasonable to expect that in patients, I believe LN2 and LN3, we could still continue to see some improvement in terms of the proteinuria as patients continue to be followed?

Yes. Let me try to address it, and if Julie has something to add, that's great. So keep in mind that gamma delta-1 T-cells have tissue tropism, including the kidneys. By the way, we did confirm this in our RCC study with a different gamma-delta 1 cell therapy, where we saw significant exposure in the kidney.

What does that mean? If you look actually at Novartis' data set, they saw a 50% reduction in the patient -- in the percent of patients with proteinuria at month 12. What we saw three out of five, i.e., 60% of the patients with complete renal response at month 6. So this only may suggest that patients might get better sooner on the Lupus Nephritis components. So we're very, very happy with that. Regarding the continued improvement in the kidney function, it's something that we have seen and I can tell you that today, all the responses are ongoing or even getting better.

The other point I might mention to you, there was one slide that we presented that show the RAxul data. I discussed the right side of the slide, where I show this 50% reduction in proteinuria. I want to point your attention to the left side of this slide, where actually Novartis outlined in blue, the reduction of SLEDAI in the SLE patient. And in green, the reduction in SLEDAI in the LN patients. And as you can see, the reduction in the LN patients, there is like a little bit of a plateau around 4. And based on the data that we see, you can see that this is a more persistent proteinuria. So overall, our data compare very well to Novartis, if only maybe you see a faster resolution of the proteinuria in patients. Great question, John.

And then, just one quick follow-up question. Can you comment on how you taper the immunosuppressant before treatment with auto cell. And also importantly, how does this compare to an autologous CAR-T where patients may be off of immunosuppression, may need to be off of immunosuppression during manufacturing. Just in terms of ease of use for both the patient and the physician.

Yes, yes. Let me walk me through the journey, because it's very different. So generally, with autologous cell therapies, you want patients to discontinue immunosuppressants, let's say, a month before the leukapheresis, because you want to get their cells with good fitness. So you stop immunosuppressants for a month, then you need to schedule a leukophoresis chair and fight for the resources in the hospital, because there's not a lot of leukophoresis chairs in terms of capacity. Then you get the leukophoresis. Then you wait approximately a month before starting the treatment. So the patient needs to be for approximately 2 months of immunosuppressants before they start the study.

Then you need to schedule time with HemOnc, because these are autologous alpha-beta T-cells and you never know who's going to get the high-grade ICANS, right? It's -- you just never know. We see these events of Grade 3 and Grade 4 ICANS with autologous cell therapies. So they need to get resources from HemOnc to really watch over these patients and manage all of their toxicities.

In our case, it's very simple. Patients get into screening. Screening is 28 days during the screening that take off their immunosuppressants. And then, they come and after 3 days of conditioning, they get a single dose of ADI-001, and it's very well tolerated, very well tolerated. No ICANS and just two cases of CRS, which were just Grade 1 and simple fever. So very, very different. In our case, you just stop immunosuppressants during screening and started treatment. Much, much, much, simpler for the patient and for the treating physician.

Your next question will come from Robert Driscoll with Wedbush.

Some really nice data here. I just wondering if there is a way to kind of characterize which patients may have more severe existing kidney damage at baseline just in terms of maybe predicting which of those kind of lupus nephritis patients kind of may have those more persistent proteinuria scores following treatment?

Julie, any feedback you can provide here? I think the field is really young in trying to define who will respond and who will not.

Yes, I tend to agree in clinical practice, when you do biopsies, you look at chronicity and activity scores, but none of that has panned out to really correlate exactly with outcome.

Yes. But Robert, I would just add to you, having three CRRs out of five is amazing, but also two -- if two of the patients are at partial renal response, it's also great, because keep in mind dose immunosuppressants and corticosteroids have such significant toxicities. And in many cases, patients with LN die in their 50s. In many cases, because of an infection, because they have been immunosuppressed for decades. So if you can give them one treatment and only halt the disease progression, and they stop taking these chronic immunosuppressants and high-dose steroids, that's still an amazing outcome, like we want to prevent disease progression and further organ damage in these patients.

So even if you can predict who is going to be a partial renal response still, it's great help for these patients to be able to stop their chronic immunosuppressants and steroids.

Yes. That makes sense. And then, maybe just sneak one more in. Just on the dose going forward. Just how are you thinking about that?

Sure. So we're very, very happy with the efficacy that we're seeing and the safety per protocol. We're increasing the dose to 1e9. We already started dosing the 1e9 dose. But based on the data so far, we expect a recommended Phase II dose to be 3e8. We can see us improving efficacy more. This is as good as it gets when you compare it to all the autologous cell therapies. So that's currently what we expected to recommend Phase II dose of 3e8.

Your next question will come from Reni Benjamin with Citizens JMP.

Congratulations Chen and team on the data. A couple of questions for you, I guess. One, any thoughts on potential re-dosing of these patients, especially the partial renal responses? And as you think about the 25 sites that are now activated and kind of the current enrollment trends, as we think about the next update that's coming in the first half of '26, how many more patients do you think we might see?

And in terms of durability, what do you think is the kind of durable response rate?

Reni, you got to stop. You asked three questions. So let's go one by one. So the first one, can you repeat? Let's just go one by one.

Yes. Any thoughts on redosing?

No. We don't have right now any thoughts about redosing. This is single-dose treatment, and it produced great data so far. We certainly have the ability to redose. This is an off-the-shelf product and there is no prevention for people to redose in the future. But right now, this protocol is a single administration. So that was one question.

And then, the next question was regarding site. So currently, we have -- we actually have more interest for more sites that are interested in joining the study. So we expect to continue to increase the number of sites. We see increased enrollment -- increased interest in enrollment to the study patients -- or sorry, investigators that provided one patient to the study, very quickly come with their second patient with LN or SLE or with patients with systemic cirrhosis and now we see patients interested with myositis and ANCA vasculitis. So this process, once you have a drug that's off-the-shelf well tolerated and provides these type of efficacy, it just kind of fit itself and you see more and more interest from patients and from physicians and from sites.

So we're actually very optimistic about the pace of enrollment here. I can say that, if you told me that the three patients per month, let's put it this way as of now, enrolling three patients per month wouldn't be something that wouldn't be normal for the company, but we have not guided for how many patients will have in the first half of next year update. But I would -- I believe that this data that we're presenting today de-risks the pivotal study in a very significant way.

And next -- in the first half of next year, following the discussion with the FDA and the additional patients that will present the pivotal study will be completely de-risked, but we'll see that in the very near future. That was your second question, and there was a third, if I remember.

Yes. Thanks. As we think about the competitive landscape, the fact that there are registrational studies, kind of, ongoing right now. How do you see 001, maybe threading that needle in a world, right, not just for clinical execution, but in a world where, let's say, there's multiple cell therapies approved, right, in something like LN?

Reni, we don't need to thread the needle. Because the tolerability that we see here should enable us to dose in outpatient settings. This opens the universe to so many sites that are interested in joining these studies, but just so far, don't have the capabilities, because they don't have the leukophoresis bed and they don't know how to manage these CRS and ICAN. So from a clinical execution, we see a great potential.

In clinical practice, we would expect the same advantage to continue, because if you're a patient, why would you stop immunosuppressants for 2 months and you might flare, then do the leukophoresis and then be concerned about CRS and ICANS. If you can just take something that's available off-the-shelf and is safer and doesn't require all the hassle around the total cell therapy. So we believe that this actually positions us for great success with an off-the-shelf and differentiated product.

Your next question will come from Soumit Roy with Jones Trading.

Congrats on durable data, especially the robust immune reset. A quick one on the CRR EGFR definition. Is it going to be in line with Cabaletta autologous type cell therapy names where greater than 60 ml per minute? Or is it are Roche and GSK, they are doing it at 85 to 90 ml per minute. Is that something still up in the air and needs to be sorted out with the FDA?

No, I don't think so, and Julie might correct me here. The complete renal response, that definition that we're using is the one that's applicable for pivotal studies essentially proteinuria needs to go to below 0.5. And EGFR needs to be stable, i.e., don't want to see a reduction of more than 15% in the EGFR. That's the definition in pivotal studies. That's a definition that we're using. And separately, EGFR above 60 is considered in the normal range, but that's unrelated to the definition of complete renal response.

Julie, anything that you would correct here?

No, that's absolutely correct. Everything above 60 is normal.

Got it. One quick one is the dose levels for the patients 2 and 3. If you can remind us, was this 3 million? Or was it lower versus 1, 4 and 5 patients?

Yes. It's actually on the first slide, the dose for the first 3 patients with LN was 1e8, that's 100 million CAR-T cells, and the dose for the next 2 patients was 3e8, which is 300 million CAR-T cells.

Our final question will come from Robert Burns with H.C. Wainwright.

Congrats on the data. Just one for me, if I may. So given the strength of this data set as well as the allogeneic differentiation or 001 relative to the autologous competitors, how are you thinking about potential BD opportunities for 001, both in the U.S. as well as ex U.S.?

Yes Absolutely, Robert. Well, certainly, I can tell you that there is generally interest in BD, but we're going to be opportunistic. When it comes to BD, we absolutely want to make sure we maximize shareholders' value. We believe that the valuation of the company and that's reflected in the program right now is completely not in even remotely even close to the ZIP code where it should be, but we'll be listening to BD opportunities. But again, we want to execute, build value and generate the right returns for patients and progress aggressively with this program. We have the sites engaged. We have more sites engaged, we know what a pivotal study looks like. We can execute on a pivotal study. So Robert, we want to run.

Awesome. I love hearing that. Thank you guys.

We have reached the top of the hour. This concludes today's call. Thank you for joining us, and goodbye.